The present invention relates to novel thioester derivatives of thiazolyl acetic acid of the general formula (I). The invention also relates to a novel process for preparation of the thioester derivatives. The reactive thioester derivatives are useful as intermediate for the preparation of cephalosporin antibiotics having the formula (II). In addition, the present invention also relates to a process for preparation of cephalosporin antibiotics using the said thioester derivatives. 
wherein, R1 represents H, trityl, CH3, CRaRbCOOR3 
(Ra and Rb independently of one another represents hydrogen or methyl and R3 represents H or C1-C7 alkyl).
R2 represents C1-C4 alkyl or phenyl.
Acid chlorides, anhydrides, esters, amide etc. are reported in the chemical literature for activation of carboxylic acid of formula (IV). Activation in the form of acid chloride required protection and deprotection of NH2 group. 
Activation of acid (IV) is reported by SO2Cl2,/DMF in U.S. Pat. No. 5,856,502 and SOCl2/DMF in U.S. Pat. No. 5,037,988. These processes suffer the limitation of using harmful and pungent smelling chemicals like SOCl2, SO2Cl2 along with solvents like benzene, toluene, etc. and stringent conditions required for carrying out the reactions at commercial scale.
In U.S. Pat. Nos. 4,576,749 and 4,548,748 the acid of formula (IV) have also been activated by reacting with 1-hydroxybenzotriazole (HOBT) or 2-mercaptobenzothiazole (MBT) in the presence of dicyclohexylcarbodiimide (DCC) to produce reactive ester of the acid (IV) which then reacted to cephem moiety to prepare cephem antibiotics, but the processes are time consuming and with low yields, hence not suitable.
U.S. Pat. No. 4,767,852 discloses a process for production of cephems by acylating 7-amino-3-cephem-4-carboxylic acid with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (MAEM). Similarly, U.S. Pat. No. 5,026,843 (1991) disclosed a process for preparing ceftriaxone disodium hemiheptahydrate by acylation of ACT by using MAEM as acylating agents in good yield and quality. Thus MAEM has become the standard acylating agent for the preparation of cephalosporins having an oximino group and a 2-aminothiazolyl group in 7-position of cephem compounds.
However, the synthesis of MAEM from acid (III) and 2,2xe2x80x2-dithio-bis-benzothiazole involves use of costly condensing agent triphenylphosphine (TPP). Moreover, during condensation of MAEM with 7-amino-3-cephem-4-carboxylic acid compound (III), a toxic compound MBT is also produced as a byproduct, see e.g., Chemical Abstracts, 111, 19243P (1989) which is difficult to remove completely.
Thus it is evident that the procedures described in the prior art for preparation of these antibiotics are complex, involving protection, deprotection and are associated with toxic byproduct generation. Hence there is a need to develop new acylating agents which are capable of transferring the 2-aminothiazolyl moiety to cephem compounds of formula (III) in good yield but without producing this toxic by product. On the similar lines, a new thioester was reported by D. G. Walker, Tet. Lett. 1990, 31, 6481 to, acylate the cephem moiety to get cefepime sulfate but yields obtained by using this thioester were in the range of 54-73% which cannot be considered as good yield to operate a process at commercial scale. The use of this thioester was reported in the Tet. Lett. 1990, 31, 6481 only for cefepime and not for other cephalosporins. This thioester was exploited in U.S. Pat. No. 5,869,649 for making three other important cephem antibiotics.
The primary objective of the invention is to prepare novel thioester derivatives of thiazolyl acetic acid of the general formula (I), which would be better than the existing reactive derivatives and suitable for being used in the manufacture of cephalosporin antibiotics.
Another objective of the present invention is to provide a process for the synthesis of thioester derivatives of formula (I) from thiazolyl acetic acid of the general formula (IV) and thio-oxadiazoles of the general formula (VI).
Yet another objective of the present invention is to provide a simple, high yielding and cost-effective process for the preparation of cephalosporin antibiotics of the general formula (II).
Still another objective of the present invention is to produce cephalosporin antibiotics that are highly pure and free from toxic byproducts.
One more objective of the present invention is to provide a process for the preparation of cephalosporin antibiotics of the general formula (II) from the said novel thioester derivatives.
The present invention provides novel thioester derivatives of thiazolyl acetic acid of the general formula (I). The invention also provides a method by which, the said thioester derivatives can be prepared. The thioester derivatives so obtained are reacted with 7-amino-cephem carboxylic acids of the general formula (III) to produce cephalosporin antibiotic compounds having the general formula (II).
The present invention provides new thioesters of the general formula (I) that are prepared by a novel method which has not been reported in the prior art. The use of these compounds in the process for preparing cephem derivatives renders the process entirely new and different from others. The novel derivative of thiazolyl acetic acid is represented by the formula (I) 
wherein, R1 represents H, trityl, CH3, CRaRbCOOR3 (Ra and Rb independently of one another represents hydrogen or methyl and R3 represents H or C1-C7 alkyl).
R2 represents C1-C4 alkyl or phenyl
The synthesis of compound (I) is achieved by reacting thiazolyl acetic acid of the general formula (IV) with thio-oxadiazoles of the general formula (VI) in organic solvent in presence of an organic base. The condensation is done with the help of a condensation agent of the formula (V). When the above reaction is carried out, the temperature is maintained between xe2x88x9210xc2x0 and +30xc2x0 C. 
wherein, R1 represents H, trityl, CH3, CRaRbCOOR3 (Ra and Rb independently of one another represents hydrogen or methyl and R3 represents H or C1-C7 alkyl).
R2 represents C1-C4 alkyl or phenyl 
wherein R4 is CH3, xe2x80x94CHxe2x95x90CH2, CH2OCH3, CH2OCOCH3, 
or a standard cephalosporin substituent.
R5 is hydrogen, salt or carboxylic protecting group.
R6 is hydrogen or silyl.
In an embodiment the organic solvent is selected from the group comprising dichloromethane, tetrahydrofuran, dioxane, N,N-dimethylformamide, acetone, carbon tetrachloride and mixtures thereof.
In another embodiment the condensation agent is bis-(2-oxo-oxazolidinyl) phosphinic chloride.
In still another embodiment the organic base is selected from triethylamine diethylamine, tributylamine, pyridine, N-alkylanilines, 1,8-diazabicyclo[5.4.2]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, N-methylmorpholine and mixtures thereof.
The compound (I) so obtained is reacted with 7-amino cephem carboxylic acids of the general formula (III) in organic solvent in presence of organic base to obtain cephalosporin antibiotics of general formula (II).
For protection of carboxylic group as ester, following group can be used which are easily converted into free carboxylic acid, e.g. p-methoxybenzyl, p-nitrobenzyl, diphenyl methyl, phenacyl trimethylsilyl. 
wherein, R1, R2 R4, R5, and R6 are as defined above.
The present invention provides a method by which cephalosporin antibiotics are obtained in high purity (95-99%) and excellent yield (79-95%) without the necessity for protecting the amino group of the acylating agents and the production of toxic byproduct namely 2-mercaptobenzothiazole is avoided.
The substituent R4 in cephem compound (III) represents methyl, acetyloxymethyl, methoxymethyl, vinyl, pyridylmethyl, propenyl, 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-thiol, furanyl-2-carbonyl thiol or a standard cephalosporin substituents defined by R4. In general, R4 represents xe2x80x94CH2xe2x80x94X wherein X is a residue of any organic or inorganic nucleophilic compound, e.g., halogen, hydroxy, cyano, mercapto, azido, amino, etc. Furthermore, X may preferably represent residue of any 5 or 6 membered heterocyclic thiol.
The heterocyclic thiol contains one to four hetero atoms selected from a group of nitrogen, oxygen and/or sulfur. Some of the examples of five membered ring are 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1H-tetrazolyl, 1,2,4-tetrazolyl, 1,2,3-tetrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, etc. The six membered heterocyclic ring can be exemplified by pyridyl, pyrimidyl, pyridinyl-N-oxide, etc.
R5 represents hydrogen, salt or a standard carboxylic protecting group.
R6 is hydrogen or silyl.
The condensation of cephem compound (III) with thioester (I) is performed by two different methodologies (a) by acylating the compound (III) (when R6 is H) with compound (I) in aqueous organic solvent; (b) by acylating compound (III) (when R6 is silyl) with compound (I) in aprotic organic solvents. Both the approaches are comparable and afforded excellent yields and purities of cephem antibiotics (II).
Acylation of compounds of formula (III) (when R6 is H) is performed in presence of a water miscible solvent like tetrahydrofuran (THF), acetonitrile, acetone, dioxane, N,N-dimethylformamide etc. but the preferable solvents are THF and acetonitrile.
In an embodiment of the present invention, acylation of compound of formula (III) (when R6 is silyl) is carried out in aprotic organic solvents like halogenated hydrocarbons, toluene, alkyl ethers etc., but the preferred solvent is dichloromethane. Suitable silylating agents used for the reaction are hexamethyldisalazane, bis(trimethyl)silylacetamide and trimethylsilyl chloride.
In another embodiment of the present invention, the organic base may be selected from triethylamine, diethylamine, tributylamine, N-alkylpyridine, N-alkylanilines, 1,8-diazabicyclo[5.4.2]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, N-methylmorpholine, 1,4-diazabicyclo[2.2.2]octane, 4-dimethylamino pyridine and mixtures thereof.
The utility of the novel thioesters of 2-mercapto-5-phenyl-1,3,4-oxadiazole was tried in various coupling reactions of carboxylic acids and amines. Most of amide formation reactions have shown good results. L-alanine, 5-methylisoxazole-4-carboxylic acid, 2-thienylacetic acid, etc. are some of the compounds, which have been activated by above mentioned thiol. Few results are summarized in the following table.
In an embodiment, R4 represents any of methyl, vinyl, methoxymethyl, pyridylmethyl, acetyloxymethyl, (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl) thiomethyl, furylcarbonyl thiomethyl or a standard cephalosporin substituent.
In another embodiment, R1 represents H, trityl, CH3, CRaRbCOOR3 (Ra and Rb independently of one another represents hydrogen or methyl and R3 represents H or C1-C7 alkyl).
In still another embodiment, R5 is hydrogen or alkali metal salt.
In yet another embodiment, the alkali metal salts are selected from sodium, potassium and lithium salts.
In another embodiment, the compound of formula II is a syn isomer.
In still another embodiment, R6 is silyl, the acylation is achieved by doing the reaction in aprotic organic solvent like halogenated hydrocarbon, toluene, alkyl ether preferably in dichloromethane.
In another embodiment, R2 is methyl and R4 represents any of (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thiomethyl, and purification of this compound is achieved by dissolving the crude product in mixture of water and water miscible organic solvent selected from acetone, IPA, dioxane and mixture thereof.
In another embodiment, the organic base is selected from the group consisting of triethylamine, N-methylmorpholine, N-methylpyridines, N-methylanilines, 1,5-diazabicyclo[4.3.0] non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 4-dimethylaminopyridine, and mixtures thereof.
In an embodiment, R2 is methyl, R4 is (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3-yl)thiomethyl, the colour impurities are separated at xe2x88x9210xc2x0 C. to 0xc2x0 C. and precipitation by water miscible organic solvent selected from acetone, IPA, dioxane and mixture thereof.
Thus the present invention provides novel thioester derivatives of thiazolyl acetic acid of the general formula (I), also, the invention provides a method by which the said thioester derivatives can be prepared by reacting thiazolyl acetic acid of the general formula (IV) with 2-mercapto-5-substituted-1,3,4-oxadiazole of the general formula (VI) (preparation of VI, J. Am. Chem. Soc., 1955, 77, 400) in a solvent, in presence of an organic base and with the help of condensation agent bis- (2-oxo-oxazolidinyl) phosphinic chloride of the formula (V) (preparation of V, Synthesis, 1980, 547). The so obtained thioester derivatives are reacted with 7-amino-cephem carboxylic acids of the general formula (III) to produce cephalosporin antibiotic compounds having the general formula (II). The cephalosporin antibiotics so obtained are of high purity (95-99%). The method gives an excellent yield (79-95%) of cephalosporin without necessitating for the protection of the amino group of the acylating agents, and the toxic byproduct 2-mercaptobenzothiazole is not produced.
Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure. However, since the major characteristic feature of the present invention resides in the use of novel reactive thioester derivatives of thiazolyl acetic acid of the general formula (I) in preparing the cephalosporin antibiotics, the technical scope of the present invention should not be limited to the following examples.